The use of synthetic cannabinoid receptor agonists, first developed as research tools and later sprayed on plant material and sold as a legal alternative to cannabis, has increased in recent years, despite attempts to limit their commercial availability. This is due at least in part to the common perception of cannabinoids as a soft drugs with relatively mild withdrawal symptoms. However, a growing literature indicates Cannabis Use Disorder affects many users, the primary symptoms being emotional (e.g., anxiety, depression, agitation), somatic (e.g., gastric upset, sleep disturbance), and cognitive (e.g., cravings for cannabis). Not surprisingly, alleviating the aversive symptoms brought about by abstinence is common cause of relapse. Thus, there is a need to develop new treatments for cannabinoid dependence. Current preclinical research on cannabis dependence uses somatic outcomes to quantify cannabis withdrawal. These models have been useful but do not explore the emotional aspects of cannabinoids withdrawal that are most salient in humans and contribute directly to relapse. Our preliminary data indicate that withdrawal from the phytocannabinoid ?9-tetrahydrocannabinol (THC), or the synthetic cannabinoid JWH-018, significantly decreases marble burying, a proxy measure of agitation, and increases struggling in the tail suspension test. The goal of Aim 1 is to fully characterize the behavioral effects of synthetic cannabinoid withdrawal on preclinical measures of emotionality and motivation. We will treat mice repeatedly with the prototypical synthetic cannabinoid agonist JWH-018 or CP55,940 and induce precipitated and spontaneous withdrawal, to quantify withdrawal behaviors in a battery of tests to model emotion, motivation, and somatic signs of withdrawal. In addition to behavioral interventions, adjuvant therapies have been used with much success to reduce drug dependence. The goal of Aim 2 of the proposed studies is to normalize JWH-018 withdrawal-induced behavioral changes by positive allosteric modulation of the CB1 receptor. We propose to administer a positive and a negative allosteric modulator to mice undergoing withdrawal, and to test alterations in behavioral assays that our unpublished preliminary data indicate are altered by cannabinoid withdrawal. It is expected that positive allosteric modulation will attenuate JWH-018 withdrawal-induced behavioral changes. The successful completion of the proposed project will yield preliminary data for larger scale neurobehavioral project, with the goal of informing human cannabinoid dependence research.